Case Histories - Freeze-drying of Pharmaceuticals and Biopharmaceuticals - page 165

12.2 Choice of Formulation
A detailed account, describing the stepwise development of a freeze-
drying process for a protein drug, has been published previously by the
author's laboratory. 157 The following account is based on the cited
report but is limited only to its salient points. The factors that must be
considered during an initial formulation stage have already been dis-
cussed in other chapters. Pharmacokinetic aspects apart, they include
the important decision whether to aim for physical homogeneity or
heterogeneity, expressed by amorphous or crystalline end products,
respectively. For biopharmaceutical products, especially those based
on proteins, this choice seldom arises because crystallisation is generally
not an option. For parenteral products, important questions concern the
isotonicity and the volume of reconstituted solution to be administered.
12.3 Process Cycle Optimisation
Optimisation in this context usually means the shortest cycle commen-
surate with an end product of the desired quality. As discussed before,
the only process variables that permit direct control are the shelf
temperature, the chamber pressure and the duration of the total process
cycle. Other things being equal, process control by adjustment of the
chamber pressure is to be preferred over control by shelf temperature.
During the secondary drying stage, however, the temperature needs to
be raised because the diffusion of water from the solid cake is hardly
affected by pressure. The heating rate must however be carefully con-
trolled, so that collapse is avoided. The completion of the process may
be judged by the residual water content, which is of course an indirect
measure of the glass transition temperature T g .
12.4 Concurrent Product and Process Refinement
The development here described involved a 4-amino-methylthioxant-
hone derivative (WIN) with novel cytotoxic antineoplastic activity. Its
properties had been evaluated in clinical studies in the form of a
stabilised solution formulation, supplied in ampoules at a concentration
of 2.5 mg ml 1 in citrate buffer (pH 5.5). Unless kept refrigerated
(2-81C), a precipitate of drug dimer was gradually formed during storage.
The main aim of the freeze-drying optimisation process was to provide a
commercially acceptable drug that could be stored at ambient tempera-
ture. Three trial formulations were prepared, as detailed in Table 1.